1. Field of the Invention
The present invention relates generally to novel methods of administering oxybutynin, to novel forms of oxybutynin and novel dosage forms containing oxybutynin designed for delivery via the pulmonary route. More specifically, the present invention comprises novel forms of oxybutynin in combination with one or more pharmaceutically effective agents. The invention will be described in particular in connection with pulmonary delivery of oxybutynin for treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD), although other uses such as prophylactic, therapeutic or ameliorative treatment of incontinence and intestinal hypermotility, i.e. irritable bowel syndrome, also are contemplated.
2. Description of the Prior Art
Oxybutynin is a racemic compound of the chemical formula 4-diethylaminobut-2-butynyl phenylcyclohexyl-glycolate:

Oxybutynin is an anticholinergic medication that traditionally has been used to treat urinary incontinence, urge incontinence, frequency and over-active bladder symptoms of incontinence (hereinafter singly and collectively referred to as “urge urinary incontinence”). Oxybutynin acts by decreasing muscle spasms of the bladder. It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor. It also has weaker direct spasmolytic effects on bladder smooth muscle as a calcium antagonist and local anesthetic, but at concentrations far above those used clinically. It is available orally in generic formulation and as the chloride salt, and as the brand-names DITROPAN® and DITROPAN XL®, and as a transdermal product as a patch under the brand-name OXYTROL® or as a gel under the brand name GELNIQUE™.
Oxybutynin currently is administered in oral formulation as a tablet or multiple tablets and a syrup, or transdermally as a patch or topical gel for treating urge urinary incontinence. However, oral delivery of a therapeutically active amount of oxybutynin suffers from a number of disadvantages:
(1) Oxybutynin administered in an oral formulation is absorbed from the intestinal track at an undesirably slow and uneven rate with a variable metabolism that leads to undesirable variations in blood levels and undesirably high dosage rates to achieve a therapeutic response leading to undesirable side effects;
(2) Oxybutynin administered in an oral formulation does not produce desirably high blood levels in a desirably short period of time;
(3) Oxybutynin administered in an oral formation may result in a significant amount not reaching targeted tissues because it is being wasted by metabolism or excretion;
(4) Oxybutynin administered in an oral formation is contraindicated for patients with gastrointestinal obstruction disorders because of the risk of urinary retention; and
(5) Oxybutynin administered in oral formulation requires chronic dosing with significant and severe side effects, including dry mouth (xerostomia), constipation, mydriasis, blurred vision, drowsiness, nausea, palpitations, tachycardia and dizziness.
(6) Oxybutynin administered in the oral formulation is subject to first pass metabolism, resulting in the formation of metabolite N-desethyloxybutynin (DEO) which has been attributed to cause the majority of the aforementioned side effects.
As a result, many patients discontinue oral anticholinergic therapy. These adverse effects have been associated with relatively high levels of oxybutynin's primary metabolite, DEO, which circulates in concentrations approximately 4 (oxybutynin ER) to 10 (oxybutynin IR) times that of the parent compound. DEO has been shown to have a greater affinity and binding duration at receptors in the salivary glands than does oxybutynin. In other words, the metabolite DEO has shown to have a higher side effect-to-efficacy ratio than the parent compound oxybutynin. Levels of DEO in oral and transdermal therapy have been reported to be approximately 10-40 ng/mL and 3 ng/mL, respectively. To completely eliminate the side effect concerns of this drug, it would be advantageous to decrease the DEO levels in systemic circulation to below those found in current therapies (i.e. below 3 ng/mL).
Moreover, there are other disadvantages to current oral administration of oxybutynin, including:
(7) Oxybutynin administered in an oral formation is administered as a tablet or multiple tablets which may lack the desirable ease of administration because some people may dislike the swallowing of tablets, or may have difficulty swallowing tablets, or are unable to swallow tablets, or may require a liquid to assist swallowing of tablets; and
(8) Oxybutynin-containing tablets also contain several inactive ingredients, including significant amounts of lactose, corn starch, magnesium silicate, magnesium stearate, and talc which may be considered undesirable because some people may dislike or be allergic to one or more of these inactive ingredients that comprise the oxybutynin tablets.
Transdermal delivery of oxybutynin has many of the aforesaid disadvantages. Additionally, some patients suffer skin irritation from transdermal patches, have difficulty maintaining and tolerating patch-to-skin contact, or dislike the aesthetics of a transdermal patch.
Bronchoconstriction, a hallmark of pulmonary disease such chronic obstructive pulmonary disease and asthma, involves the narrowing of air passages (bronchi and bronchioles) in the lungs due to muscle contraction. Often times the muscle contraction is a result of activation of muscarinic receptors on the membranes of smooth muscle cells. This results in the limitation of air flowing to and from the lung and causes shortness of breath and overall difficulty in breathing.
Pulmonary disease includes, but is not limited to, acute bronchitis, acute respiratory distress syndrome (ARDS), asbestosis, asthma, atelectasis, aspergilliosis, bronchiectasis, bronchiolitis, bronchopulmonary dysplasia, byssinosis, chronic bronchitis, coccidiomycosis, chronic obstructive pulmonary disease (COPD), cystic fibrosis, emphysema, eosinophilic pneumonia, hantavirus pulmonary syndrome, histoplasmosis, human metapneumovirus, hypersensitivity pneumonitis, influenza, lung cancer, lymphangiomatosis, mesothelioma, necrotizing pneumonia, nontuberculosis Mycobacterium, pertussis, pleural effusion, pneumoconiosis, pneumonia, primary ciliary dyskinesia, primary pulmonary hypertension, pulmonary arterial hypertension, pulmonary fibrosis, pulmonary vascular disease, respiratory syncytial virus, sarcoidosis, severe acute respiratory syndrome, silicosis, sleep apnea, sudden infant death syndrome, and tuberculosis. The most common lung diseases generally comprise asthma, bronchitis, COPD, emphysema, and pneumonia.
Of all pulmonary diseases, the most prevalent appears to be COPD. According to the World Health Organization estimates in the year 2004, 64 million people had COPD and 3 million people died of COPD. WHO predicts that COPD will become the third leading cause of death worldwide by 2030. The Merck Manual (2011) provides that an estimated 12 million people in the US have COPD and describes COPD as the 4th leading cause of death, resulting in 122,000 deaths in 2003 compared with 52,193 deaths in 1980. From 1980 to 2000, the COPD mortality rate increased 64% (from 40.7 to 66.9/100,000). Prevalence, incidence, and mortality rates increase with age and though prevalence is higher in men, total mortality is similar in both sexes. Incidence and mortality are generally higher in caucasians, blue-collar workers, and people with fewer years of formal education, probably because these groups have a higher prevalence of smoking. COPD is increasing worldwide because of the increase in smoking in developing countries, the reduction in mortality due to infectious diseases, and the widespread use of biomass fuels.
Current therapeutic agents for COPD predominately comprise bronchodilators administered via inhalation, including inhaled long-acting beta2-agonists (LABA) or long acting muscarinic antagonists (LAMA). Although oxybutynin is a LAMA, no effective pharmaceutical form, or method of administration has heretofore been developed to treat COPD using oxybutynin. Many diseases of the respiratory tract are known to respond to treatment by the direct application of therapeutic agents. As these agents are most readily available in dry powdered form, their application is most conveniently accomplished by inhaling the powdered material through the nose or mouth. This powdered form can result in the better utilization of the medicament in that the drug is deposited exactly at the site desired and where its action may be required; hence, very minute doses of the drug are often equally as efficacious as larger doses administered by other means, with a consequent marked reduction in the incidence of undesired side effects and medicament cost. In addition, a drug in dry powder form may be used for treatment of diseases other than those of the respiratory or pulmonary system. When the drug is deposited on the very large surface areas of the lungs, it may be very rapidly absorbed into the blood stream; hence, this method of application may take the place of administration by injection, tablet, or other conventional means.
Although some forms of oxybutynin hydrochloride compositions have been contemplated for administration in dry powder form, no such forms have yet been successfully reduced to practice. There remains a need for oxybutynin therapeutic compositions that are clinically effective and having the appropriate physiochemical properties.
Thus, there is a need for improved delivery of oxybutynin, which will provide enhanced bioavailability, minimized variations in blood levels, and achieve more rapid onset of activity, as compared to oral dosage or transdermal dosage forms, while at the same time providing relative ease of administration and reduced side effects compared to current oral and transdermal delivery methods for administering oxybutynin.